Immunotherapy In Metastatic Colorectal Cancer Research Articles

68Ga-FAPI PET imaging monitors response to combined TGF-βR inhibition and immunotherapy in metastatic colorectal cancer.

68Ga-FAPI PET imaging monitors response to combined TGF-βR inhibition and immunotherapy in metastatic colorectal cancer.

Update on Targeted Therapy and Immunotherapy for Metastatic Colorectal Cancer.

Metastatic colorectal cancer remains a deadly malignancy and is the third leading cause of cancer-related death. The mainstay of treatment for metastatic colorectal cancer is chemotherapy, but unfortunately, even with recent progress, overall survival is still poor. Colorectal cancer is a heterogeneous disease, and the underlying genetic differences among tumors can define the behavior and prognosis of the disease. Given the limitations of cytotoxic chemotherapy, research has focused on developing targeted therapy based on molecular subtyping. Since the early 2000s, multiple targeted therapies have demonstrated efficacy in treating metastatic colorectal cancer and have received FDA approval. The epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), and DNA mismatch repair pathways have demonstrated promising results for targeted therapies. As new gene mutations and proteins involved in the oncogenesis of metastatic colorectal cancer are identified, new targets will continue to emerge. We herein provide a summary of the updated literature regarding targeted therapies for patients with mCRC.

68Ga-FAPI PET imaging monitors response to combined TGF-βR inhibition and immunotherapy in metastatic colorectal cancer.

BACKGROUNDImproving and predicting tumor response to immunotherapy remains challenging. Combination therapy with a transforming growth factor-β receptor (TGF-βR) inhibitor that targets cancer-associated fibroblasts (CAFs) is promising for the enhancement of efficacy of immunotherapies. However, the effect of this approach in clinical trials is limited, requiring in vivo methods to better assess tumor responses to combination therapy.METHODSWe measured CAFs in vivo using the 68Ga-labeled fibroblast activation protein inhibitor-04 (68Ga-FAPI-04) for PET/CT imaging to guide the combination of TGF-β inhibition and immunotherapy. One hundred thirty-one patients with metastatic colorectal cancer (CRC) underwent 68Ga-FAPI and 18F-fluorodeoxyglucose (18F-FDG) PET/CT imaging. The relationship between uptake of 68Ga-FAPI and tumor immunity was analyzed in patients. Mouse cohorts of metastatic CRC were treated with the TGF-βR inhibitor combined with KN046, which blocks programmed death ligand 1 (PD-L1) and CTLA-4, followed by 68Ga-FAPI and 18F-FDG micro-PET/CT imaging to assess tumor responses.RESULTSPatients with metastatic CRC demonstrated high uptake rates of 68Ga-FAPI, along with suppressive tumor immunity and poor prognosis. The TGF-βR inhibitor enhanced tumor-infiltrating T cells and significantly sensitized metastatic CRC to KN046. 68Ga-FAPI PET/CT imaging accurately monitored the dynamic changes of CAFs and tumor response to combined the TGF-βR inhibitor with immunotherapy.CONCLUSION68Ga-FAPI PET/CT imaging is powerful in assessing tumor immunity and the response to immunotherapy in metastatic CRC. This study supports future clinical application of 68Ga-FAPI PET/CT to guide precise TGF-β inhibition plus immunotherapy in CRC patients, recommending 68Ga-FAPI and 18F-FDG dual PET/CT for CRC management.TRIAL REGISTRATIONCFFSTS Trial, ChiCTR2100053984, Chinese Clinical Trial Registry.FUNDINGNational Natural Science Foundation of China (82072695, 32270767, 82272035, 81972260).

The current status and prospect of immunotherapy in colorectal cancer.

Metastatic colorectal cancer (mCRC) is a heterogeneous disease. We reviewed the current clinical trials on immunotherapy in metastatic colorectal cancer with high microsatellite instability and microsatellite stability. Owing to the advances in immunotherapy, its use has gradually expanded from second- and third-line therapies to first-line, early neoadjuvant, and adjuvant therapies. Based on current research results, immunotherapy has shown very good results in dMMR/MSI-H patients, whether it is neoadjuvant therapy for operable patients or first-line or multi-line therapy for advanced patients. KEYNOTE 016 study also showed that patients with MSS were basically ineffective in single immunotherapy. Moreover, immunotherapy for colorectal cancer may also require identification of new biomarkers.

Metastatic sites and lesion numbers cooperated to predict efficacy of PD-1 inhibitor-based combination therapy for patients with metastatic colorectal cancer.

Limited data have been used to evaluate the efficacy of immunotherapy in metastatic colorectal cancer (mCRC). Furthermore, potential markers that can be used to identify responding patients and to further improve efficacy have not been fully explored. In our study, we included a total of 97 patients with mCRC, who each received programmed death-1 (PD-1) inhibitor-based combination therapy at our center. All 12 hypermutated patients benefited from immunotherapy, with median progression-free survival (mPFS) reaching 28.3 months, regardless of liver metastasis. The objective response rate (ORR) of non-hypermutated patients was 16.5% (14/85), with an mPFS of 4.0 months. For non-hypermutated patients, multivariate analysis revealed that the combination of liver metastasis and baseline lesion number significantly stratified response and survival. The lesion-based analysis indicated that the lymph node was the most responsive, followed by the peritoneum and lung, with liver metastasis being the least responsive. None of the patients (0/7) with negative programmed ligand-1 (PD-L1) expression responded, and positive PD-L1 expression may serve as a biomarker (mPFS 5.7 vs. 2.2 months, p = 0.002) that can be used to further guide treatment in non-hypermutated mCRC with liver metastasis (CRLMs). Patients with hypermutated mCRC benefited significantly from immunotherapy, whereas the non-hypermutated cohort with liver metastasis and numerous lesions showed less benefit. The lesion sites reflected varying levels of efficacy, among which PD-L1 potentially cooperated to guide the immunotherapy of CRLMs.

Abstract 4124: Targeting the clock pathway to modulate immune response in MSI-high colorectal cancer (CRC): evidence from a preclinical in vivo model

Abstract Background. Immune checkpoint inhibitors have substantial clinical success in MSI-H/dMMR metastatic CRC. However, only a subset of patients exhibits durable responses, emphasizing the importance of identifying mechanism of innate and acquired resistance. The relation between the circadian clock and the immune system is well established. We used a syngeneic mouse model of MSI-H CRC to investigate whether a targeted enhancement of clock repressor proteins cryptochrome 1/2 (CRY 1/2) may affect tumor growth and response to anti-PD1 (aPD1). Methods. 1 × 106 MC38 cells were subcutaneously implanted into the right flank of 8 weeks old C57BL/6 mice. Mice were randomized into 1 control and 3 treatment arms (10 mice/group): A. CRY stabilizer SHP656(10 mg/kg PO, 5 days/week); B. aPD1 (100 μg/mouse IP, twice/week administered for 2 weeks); C. combination SHP656 + aPD1. Tumors from 4 mice/group were processed for tumor infiltration studies. Remaining 6 mice/group were kept for 3 weeks on maintenance aPD1 (twice/week) for survival studies. Treatment response was measured by tumor growth and survival. Treatment effects on immune cell infiltration in the tumor microenvironment (TME), functional myeloid derived suppressor cells (MDSCs) and T cells markers were investigated via flow cytometry. Results. Single agent SHP656 significantly improved survival when compared with vehicle treated mice. Similarly, combination treatment with SHP656 + aPD1 improved survival, however no additional benefit was observed over treatment with aPD1 alone. All treatment groups had a response rate of 67% (4/6 mice/treatment group showed 2-fold decrease in tumor volume 24 days after tumor challenge vs vehicle). In responders, SHP656 as a single agent or in combination with aPD1 were more effective in suppressing tumor growth as compared to aPD1 alone. Flow cytometry of 14 tumor samples demonstrated that monocytic-MDSC infiltration was significantly decreased in the combination therapy and aPD1 alone treatment arms (p = .016) as compared to vehicle suggestive of a less suppressive TME. T cell analysis suggested a decrease in intratumoral exhausted CD8+ T cells (TIM3−PD-1+, p = .02) in SHP656 + aPD1 vs vehicle, while infiltration of CD4+ T cells and T regulatory cells were not significantly affected by any treatment. Nanostring profiling on treated tumors also confirmed immune activation in responders. Conclusions. Our results show for the first time that targeting the clock pathway through modulation of CRY affects TME and tumor progression in in vivo models of MSI-H CRC. A decrease in infiltration of mMDSCs and exhausted CD8+ T cells seems to play a critical role in combination treatment efficacy but needs to be studied further. These results, suggests that pharmacological targeting of the circadian machinery holds great potential and could significantly impact the efficacy of immunotherapy in metastatic CRC. Citation Format: Shivani Soni, Francesca Battaglin, Sofi Castanon, Jae Ho Lo, Goar Smbatyan, Priscilla Chan, Meng Qu, Priya Jayachandran, Hiroyuki Arai, Natsuko Kawanishi, Wu Zhang, Steve A. Kay, Heinz Josef Lenz, Evanthia T. Torres. Targeting the clock pathway to modulate immune response in MSI-high colorectal cancer (CRC): evidence from a preclinical in vivo model. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4124.

Recent Progress in Immunotherapy for Metastatic Colorectal Cancer

Recent Progress in Immunotherapy for Metastatic Colorectal Cancer

Perspectives on Immunotherapy of Metastatic Colorectal Cancer.

Colorectal cancer, especially liver metastasis, is still a challenge worldwide. Traditional treatment such as surgery, chemotherapy and radiotherapy have been difficult to be further advanced. We need to develop new treatment methods to further improve the poor prognosis of these patients. The emergence of immunotherapy has brought light to mCRC patients, especially those with dMMR. Based on several large trials, some drugs (pembrolizumab, nivolumab) have been approved by US Food and Drug Administration to treat the patients diagnosed with dMMR tumors. However, immunotherapy has reached a bottleneck for other MSS tumors, with low response rate and poor PFS and OS. Therefore, more clinical trials are underway toward mCRC patients, especially those with MSS. This review is intended to summarize the existing clinical trials to illustrate the development of immunotherapy in mCRC patients, and to provide a new thinking for the direction and experimental design of immunotherapy in the future.

Current Status of Immunotherapy for Metastatic Colorectal Cancer

Current Status of Immunotherapy for Metastatic Colorectal Cancer

Lineage-dependent gene expression programs influence the immune landscape of colorectal cancer.

Immunotherapy for metastatic colorectal cancer is effective only for mismatch repair-deficient tumors with high microsatellite instability that demonstrate immune infiltration, suggesting that tumor cells can determine their immune microenvironment. To understand this cross-talk, we analyzed the transcriptome of 91,103 unsorted single cells from 23 Korean and 6 Belgian patients. Cancer cells displayed transcriptional features reminiscent of normal differentiation programs, and genetic alterations that apparently fostered immunosuppressive microenvironments directed by regulatory T cells, myofibroblasts and myeloid cells. Intercellular network reconstruction supported the association between cancer cell signatures and specific stromal or immune cell populations. Our collective view of the cellular landscape and intercellular interactions in colorectal cancer provide mechanistic information for the design of efficient immuno-oncology treatment strategies.

Immunotherapy in Metastatic Colorectal Cancer: Could the Latest Developments Hold the Key to Improving Patient Survival?

Immunotherapy has considerably increased the number of anticancer agents in many tumor types including metastatic colorectal cancer (mCRC). Anti-PD-1 (programmed death 1) and cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) immune checkpoint inhibitors (ICI) have been shown to benefit the mCRC patients with mismatch repair deficiency (dMMR) or high microsatellite instability (MSI-H). However, ICI is not effective in mismatch repair proficient (pMMR) colorectal tumors, which constitute a large population of patients. Several clinical trials evaluating the efficacy of immunotherapy combined with chemotherapy, radiation therapy, or other agents are currently ongoing to extend the benefit of immunotherapy to pMMR mCRC cases. In dMMR patients, MSI testing through immunohistochemistry and/or polymerase chain reaction can be used to identify patients that will benefit from immunotherapy. Next-generation sequencing has the ability to detect MSI-H using a low amount of nucleic acids and its application in clinical practice is currently being explored. Preliminary data suggest that radiomics is capable of discriminating MSI from microsatellite stable mCRC and may play a role as an imaging biomarker in the future. Tumor mutational burden, neoantigen burden, tumor-infiltrating lymphocytes, immunoscore, and gastrointestinal microbiome are promising biomarkers that require further investigation and validation.

Role of thermal ablation in the management of colorectal liver metastasis.

With a recent randomized prospective trial revealing that thermal ablative therapy as local tumor control improved overall survival (OS) in patients with unresectable colorectal cancer liver metastases (CRLM), thermal ablation continues to remain as an important treatment option in this patient population. Our aim of this article is to review the current role of the ablative therapy in the management of CRLM patients. Main indications for thermal ablation include (I) unresectable liver lesions; (II) in combination with hepatectomy; (III) in patients with significant medical comorbidities or poor performance status (PS); (IV) a small (<3 cm) solitary lesion, which would otherwise necessitate a major liver resection; and (V) patient preference. There are several approaches and modalities for ablative therapy, including open, percutaneous, and laparoscopic approaches, as well as radiofrequency ablation (RFA) and microwave ablation (MWA). Each approach and ablation modality have its own pros and cons. Percutaneous and laparoscopic approaches are preferred due to minimally invasive nature, yet laparoscopic approach has more benefits from thorough intraoperative ultrasound (US) exam as well as complete peritoneal staging with laparoscopy. Similarly, whereas high local tumor failure rate has been a major concern with RFA, MWA or microwave thermosphere ablation (MTA) have demonstrated significantly improved local tumor control due to homogenous tissue heating, ability to reach higher tissue temperatures, and less susceptible to the "heat-sink" effect. Although liver resection is the standard of care for CRLM, there have been some retrospective studies demonstrating similar oncological outcome between ablative therapy and surgical resection in very selected populations with small (<3 cm) solitary CRLM. Lastly, ablative therapy and liver resection should not be mutually exclusive, especially in the management of bilobar liver metastases. Concomitant ablative therapy with hepatectomy may spare the patients from having two-stage hepatectomy with less morbidity. The role of the thermal ablation will continue to evolve in patients with resectable and ablatable lesions owing to newly emerging technology, in addition to new systemic treatment options, including immunotherapy for metastatic colorectal cancer (CRC).

Current status of immunotherapy in metastatic colorectal cancer.

Immunotherapy focuses on selectively enhancing the host's immune response against malignant disease. It has been investigated as an important treatment modality against malignant disease for many years, but until recently its use was mostly limited to a few cancers. The advent of new immunemodulating agents in the recent past has changed the landscape for management of many solid tumors. Currently, immunotherapy offers a valuable, and in many cases, a more effective alternate to the conventional cytotoxic therapy. Colorectal cancer is a leading cause of cancer-related death. Despite progress in systemic therapy, most patients with metastatic colorectal cancer die of their disease. There is an unmet need for more effective treatments for patients with metastatic colorectal cancer. The current data support that colorectal tumors are immunoresponsive and a subset of patients with advanced disease achieve long term benefit with immunotherapy. This review aims to provide the current status of immunotherapy in patients with metastatic colorectal cancer. We researched sources published in the English language between January 2000 and August 2018 and listed within the PubMed database using combinations of the key words and reviewed the proceedings of international cancer conferences and current guidelines made by major cancer societies. In this review, we summarize the current status of research on immunotherapy in metastatic colorectal cancer and discuss various treatment modalities including checkpoint inhibitors, cancer vaccines, adoptive cell transfer, oncolytic virus therapy, and various other agents that are under investigation with a special emphasis on immune checkpoint inhibitors. Since the toxicity profile of immunotherapy is very different from conventional cytotoxic agents and could involve any organ system, we briefly review common adverse effects and their management.

Development of MGD007, a gpA33 x CD3-Bispecific DART Protein for T-Cell Immunotherapy of Metastatic Colorectal Cancer.

We have developed MGD007 (anti-glycoprotein A33 x anti-CD3), a DART protein designed to redirect T cells to target gpA33 expressing colon cancer. The gpA33 target was selected on the basis of an antibody-based screen to identify cancer antigens universally expressed in both primary and metastatic colorectal cancer specimens, including putative cancer stem cell populations. MGD007 displays the anticipated-bispecific binding properties and mediates potent lysis of gpA33-positive cancer cell lines, including models of colorectal cancer stem cells, through recruitment of T cells. Xenograft studies showed tumor growth inhibition at doses as low as 4 μg/kg. Both CD8 and CD4 T cells mediated lysis of gpA33-expressing tumor cells, with activity accompanied by increases in granzyme and perforin. Notably, suppressive T-cell populations could also be leveraged to mediate lysis of gpA33-expressing tumor cells. Concomitant with CTL activity, both T-cell activation and expansion are observed in a gpA33-dependent manner. No cytokine activation was observed with human PBMC alone, consistent with the absence of gpA33 expression on peripheral blood cell populations. Following prolonged exposure to MGD007 and gpA33 positive tumor cells, T cells express PD-1 and LAG-3 and acquire a memory phenotype but retain ability to support potent cell killing. In cynomolgus monkeys, 4 weekly doses of 100 μg/kg were well tolerated, with prolonged PK consistent with that of an Fc-containing molecule. Taken together, MGD007 displays potent activity against colorectal cancer cells consistent with a mechanism of action endowed in its design and support further investigation of MGD007 as a potential novel therapeutic treatment for colorectal cancer. Mol Cancer Ther; 17(8); 1761-72. ©2018 AACR.

Efficacy of combining radiotherapy and immunotherapy for metastatic colorectal cancer and the modulation of tumor microenvironment

Abstract Immune checkpoint blockade antibodies specific to programed death-1/ligand-1 (PD-1/PD-L1) shows durable clinical responses in various cancers but benefit only to a small portion of patients. The failure of immunotherapy is likely due to the complex network of immunosuppressive mechanisms present in advanced tumors. Radiation (RT) modifies tumor microenvironment and causes tumor antigen release, and thus augment efficacy of immunotherapy. Interleukin 12 (IL-12) and granulocyte macrophage colony-stimulator factor (GM-CSF) have shown potent antitumor activities through activating innate and adaptive immunities, as well as reprogramming myeloid cells to a phenotype that favors immune activation. The aim of this project is to compare the therapeutic efficacy of two types of combination therapy: RT combined with IL-12/GM-CSF (RT/12GM) versus RT combined with anti-PD-L1 antibody (RT/PD-L1), and to dissect the molecular mechanisms of the antitumor responses. Our data showed that RT/12GM led to tumor regression in a majority of mice with large established tumors and suppressed liver metastasis, while RT/PD-L1 could only suppress primary tumors but not metastatic tumor. Mechanistic analysis showed that RT/12GM was superior to RT/PD-L1 in inducing accumulation of CD8+ T cells in tumor and in augmenting both NK and CD8+ T cells cytotoxicity in tumor and liver. Interestingly, RT/12GM also induced infiltration of tumor-associated neutrophils (TAN) and impaired their immunosuppressive functions. Depletion experiments showed that both CD8+ T cell and TAN were required for tumor regression in RT/12GM. Together, our results demonstrate that RT/12GM represent a powerful alternative therapy against both primary and metastatic tumors.

Prediction of the efficacy of immunotherapy by measuring the integrity of cell-free DNA in plasma in colorectal cancer.

We previously reported a phase II study of a cancer vaccine using five novel peptides recognized by HLA‐A*2402‐restricted CTL in combination with oxaliplatin‐containing chemotherapy (FXV study) as first‐line therapy for patients with metastatic colorectal cancer and demonstrated the safety and promising potential of our five‐peptide cocktail. The objective of this analysis was to identify predictive biomarkers for identifying patients who are likely to receive a clinical benefit from immunochemotherapy. Circulating cell‐free DNA (cfDNA) in plasma has been reported to be a candidate molecular biomarker for the efficacy of anticancer therapy. Unlike uniformly truncated small‐sized DNA released from apoptotic normal cells, DNA released from necrotic cancer cells varies in size. The integrity of plasma cfDNA (i.e. the ratio of longer fragments [400 bp] to shorter fragments [100 bp] of cfDNA), may be clinically useful for detecting colorectal cancer progression. We assessed plasma samples collected from 93 patients prior to receiving immunochemotherapy. The cfDNA levels and integrity were analyzed by semi‐quantitative real‐time PCR. Progression‐free survival was significantly better in patients with a low plasma cfDNA integrity value than in those with a high value (P = 0.0027). Surprisingly, in the HLA‐A*2402‐matched group, patients with a low plasma cfDNA integrity value had significantly better progression‐free survival than those with a high value (P = 0.0015). This difference was not observed in the HLA‐A*2402‐unmatched group. In conclusion, the integrity of plasma cfDNA may provide important clinical information and may be a useful predictive biomarker of the outcome of immunotherapy in metastatic colorectal cancer.

CCR5 inhibition in colorectal cancer patients

Immunotherapy in metastatic colorectal cancer is a challenge. I would like to thank Dr. Mukaida for his comprehensive commentary (1) on our work (2). A couple of points were raised that I will address in this letter. Immunotherapy with new immune checkpoint inhibitors is a different approach (3) compared to the immunotherapies based on vaccination or cytokine application. While for vaccination approaches no clear benefit was identified in colorectal cancer (4), combined chemotherapy with cytokines (GOLFIG trial) showed clinical effects, albeit at the price of autoimmune side effects (5). This situation highlights the complexities of immunotherapies quite well and shows that patients with microsatellite-instable colorectal cancer are a limited subgroup within colorectal cancer (6).

Deficient Mismatch Repair and the Role of Immunotherapy in Metastatic Colorectal Cancer.

Division of colorectal cancers (CRCs) into molecular subsets yields important consequences for prognosis and therapeutic response. The microsatellite instability (MSI) immune subgroup, accounting for 15% of early-stage and 3% of metastatic CRCs, are a result of deficient cellular DNA mismatch repair (dMMR) mechanisms. dMMR CRCs are notable for greater survivability, yet lack of benefit from fluoropyrimidine-based therapy in early-stage disease as compared to proficient DNA mismatch repair (pMMR) CRCs but are substantially lethal when metastatic. The surging interest in cancer immunotherapy, particularly checkpoint blockade, has further led to a focus on MSI tumors, which are notable for their substantial T cell infiltrate. In this review, we will discuss the biologic underpinnings for the immunogenicity of dMMR CRC and the preclinical development of therapies intended to modulate this immune response. Next, we will discuss the previous and ongoing clinical trials specifically designed to evaluate immunotherapeutic treatment of dMMR CRCs. Building on the success of the early immune checkpoint inhibitor clinical trials for dMMR CRC, combinations with other anti-tumor immunotherapies may provide an even more robust response, thereby, creating an alternative treatment regimen for those who have failed standard therapies or possibly resulting in prophylactic therapies for patients with highly oncogenic hereditary mismatch repair deficiencies.

ISY5-1 - Biologics and immunotherapy in metastatic colorectal cancer

ISY5-1 - Biologics and immunotherapy in metastatic colorectal cancer

Immunotherapy of Metastatic Colorectal Cancer: Prevailing Challenges and New Perspectives.

Patients with recurring or metastatic colorectal cancer (mCRC) have strikingly low long-term survival, while conventional treatments such as chemotherapeutic intervention and radiation therapy marginally improve longevity. Although, many factors involving immunosurveillance and immunosuppression were recently validated as important for patient prognosis and care, a multitude of experimental immunotherapies designed to combat unresectable mCRC have, in few cases, successfully mobilized antitumor immune cells against malignancies, nor conclusively or consistently granted protection, complete remission, and/or stable disease from immunotherapy - of which benefit less than 10% of those receiving therapy. After decades of progress, however, new insights into the mechanisms of immunosuppression, tolerance, and mutation profiling established novel therapies that circumvent these immunological barriers. This review underlines the most exciting methods to date that manipulate immune cells to curb mCRC, including adoptive cell therapy, dendritic cell vaccines, and checkpoint inhibitor antibodies - of which hint at effective and enduring protection against disease progression and undetected micrometastases.